April 30, 2013

HIV-Infected Men at Increased Risk for Cancer

Jim Kling

Apr 30, 2013

BERLIN, Germany — HIV-infected men are at twice the risk for non-AIDS defining cancers as the general population, but highly active antiretroviral therapy has a protective benefit, according to a new study.

Little is known about how HIV infection affects the risk for non-AIDS defining cancers that don't have an infectious component. "HIV patients are living longer, and they live with chronic diseases that can compromise the immune system. People with impaired immunologic status are at increased risk for lung cancer," Laura Albini, PhD, professor of infectious diseases at the University of Brescia, Italy, told Medscape Medical News.

She presented the study results here at the 23rd European Congress of Clinical Microbiology and Infectious Diseases.

Dr. Albini and her team conducted a retrospective analysis of 5090 HIV-infected patients registered in the Local Health Authority of Brescia in Northern Italy. The researchers linked their own clinical database to the Local Health Authority general database and the Local Health Authority population-based cancer registry to diagnose nonvirus-related non-AIDS defining cancers.

They used Poisson regression to compare the risk for cancer in people infected with HIV and those in the general population living in the same geographic region.

There were 138 cancers diagnosed in 131 patients over the course of the study (42.6 per 10,000 person-years; median age at diagnosis, 49 years). The most common cancers were nonmelanoma skin (29.7%), lung (16.7%), and breast (7.3%).

More Lung Cancer

Males were at higher risk for cancer (standardized incidence ratio [SIR], 1.86; 95% confidence interval [CI], 1.55 - 2.26) than people in the general population. They also had an increased risk for lung cancer (SIR, 3.59; 95% CI, 2.36 - 5.45) and testis cancer (SIR, 3.11; 95% CI, 1.48 - 6.52).

There were no differences in prostate and breast cancers in HIV-positive men (SIR, 1.10; 95% CI, 0.53 - 2.32) and women (SIR, 0.91; 95% CI, 0.47 - 1.74).

Predictors of nonvirus-related non-AIDS defining cancers included older age (incidence rate ratio [IRR], 1.10; 95% CI, 1.08 - 1.12 for each additional year) and a shorter duration or lack of exposure to highly active antiretroviral therapy (IRR, 2.31; 95% CI, 1.38 - 3.89; P = .002). Severe immunodeficiency (CD4+ count below 50 cells/mm³) was associated with malignancies, but only in the univariate model (IRR, 1.40; 95% CI, 0.99 - 1.98; P = .057).

The increased risk for lung cancer is likely due, in part, to the fact that smoking is a common habit, but immunodeficiency also likely plays a role, according to Dr. Albini.

The results of this study are similar to those from other studies of cancer incidence in HIV-infected individuals, "although there are some differences. Other studies have shown increases in breast cancer, but this one does not," session moderator José Miró, MD, PhD, professor of medicine at the University of Barcelona in Spain, told Medscape Medical News.

The results underscore the importance of lung cancer screening in HIV patients, Dr. Miró added. "Lung cancer is really epidemic in the HIV population. Physicians should use appropriate diagnostic tools if there are any symptoms suggesting lung cancer."

Dr. Albini and Dr. Miró have disclosed no relevant financial relationships.

23rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID): Abstract O155. Presented April 27, 2013.

Source

Embolizing Vascular Shunts Relieves Hepatic Encephalopathy

Daniel M. Keller, PhD

Apr 30, 2013

AMSTERDAM, the Netherlands ― Embolizing large spontaneous portosystemic shunts can relieve hepatic encephalopathy and can keep many patients free of it for as long as they have sufficient functional liver reserve, a new study has shown.

In the 100 days after embolization, 60% of patients were free of hepatic encephalopathy. During the overall follow-up of more than 2 years, that was reduced to still a very impressive 49%. Compared with the 2-year period before embolization, both reductions were significant (P < .001), reports Wim Laleman, MD, PhD, from the Department of Liver and Biliopancreatic Disorders at University Hospitals Leuven and the Catholic University of Leuven in Belgium.

Dr. Laleman presented the study results here at the International Liver Congress 2013.

The retrospective study involved men and women from a European multicenter cohort with cirrhosis, refractory encephalopathy, and large spontaneous portosystemic shunts that were amenable to angiographic embolization. Patients were excluded if they had a surgical shunt or transjugular intrahepatic portosystemic shunt graft, portal vein thrombosis, or hepatocellular carcinoma.

Most of the cirrhosis was caused by alcohol abuse or hepatitis C. Child–Pugh score before embolization was 7.9, and model for end-stage liver disease (MELD) score was 13.2 (range, 5 - 28).

In 37 of 38 patients, embolization was achieved with a percutaneous, transhepatic, or femoral vein approach using coils, Amplatzer plugs, or matrix. The most common spontaneous shunt was splenorenal (n = 20); the rest were mesentericocaval, periumbilical, or mesentericorenal.

In addition to the reduction in hepatic encephalopathy, embolization was associated with a reduction in the number of hospitalizations, from 3.8 in the preprocedure period to 1.3 in the follow-up period (P < .001). Hospital days were reduced from 41.0 to 17.8 (P >.001).

Quality of Life

Dr. Laleman explained that quality of life is very important in the context of hepatic encephalopathy. Before embolization, almost 73% of patients had limited quality of life and were in need of help with daily activities. After embolization, only 25% of patients had limited quality of life. Autonomy increased from 21.6% of patients to 64.9%, but there was no change in complete disability (about 10% before and after embolization), he reported.

Near-term safety was excellent. There was no mortality and 8 procedure-related complications, only 1 of which was serious (hypovolemic shock after a transhepatic approach that resolved after surgical hemostasis).

Dr. Laleman put to rest concerns about possible long-term complications of worsening liver function, thrombosis, and portal hypertensive complications. "There was no increase in the presence of gastroesophageal varices and no increase in gastropathy (2 patients developed de novo varices, but this was not considered statistically significant). With regard to ascites, we saw a similar evolution, so there was no apparent increase in portal hypertensive complications," he said.

There was no change in liver function (MELD score) from before to after the procedure (13.2 vs 15.2; P = .26). Although 4 patients had thrombotic problems, this was not statistically significant.

Patient Selection

On multivariate analysis, adjusted for time between diagnosis of hepatic encephalopathy and embolization, serum albumin, International Normalized Ratio, the presence of ascites, and preprocedure Child score, the only independent predictors of recurrence of hepatic encephalopathy were sex (odds ratio [OR], 0.06; 95% confidence interval [CI], .005 - 0.971; P = .048) and pre-embolization MELD score (OR, 1.52; 95% CI, 1.073 - 2.180; P = .019).

"Embolization of these shunts is feasible, effective, and safe, provided that sufficient functional liver reserve is guaranteed," Dr. Laleman concluded. According to the investigators, patients should have a MELD score of 11 or lower to be considered for the procedure.

This is important work because it is a large study, session chair Isabelle Colle, MD, PhD, professor of hepatology and gastroenterology and head of the gastroenterology clinic at Gent University in Belgium, told Medscape Medical News.

She explained that embolization of large spontaneous portosystemic shunts is "a good treatment for patients who have really important hepatic encephalopathy and have large shunts, because they are often Child A patients.... It's clinically important that we can offer treatment to those patients without offering transplantation."

Dr. Laleman and Dr. Colle have disclosed no relevant financial relationships.

International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL). Abstract 77. Presented April 26, 2013.

Source

Also See: Shunt Correction Eases Hepatic Encephalopathy

(Ref: ViewPoints Desk)

April 30th, 2013

Once again, a combination of Gilead Sciences' sofosbuvir and Bristol-Myers Squibb's daclatasvir appears to offer the most efficacious way of treating patients with hepatitis C without the need for either interferon or ribavirin. However, Gilead has chosen not to pursue development of this combination – prompting speculation that off-label usage could prove a feasible alternative for physicians. Such an outcome is possible, say experts, although cost is likely to be a deciding – and ultimately limiting – factor.

Insight, Analysis & Opinion

Data unveiled last week showed that among a cohort of 41 patients treated with the sofosbuvir/daclatasvir combination, 40 patients were virus free (100 percent SVR) after 12 weeks of therapy. It is not the first time this combination has impressed; a year ago similarly robust data was released, providing a backdrop against which Gilead's decision to not pursue a combination therapy with Bristol-Myers Squibb was met with some consternation. See Spotlight On: Bristol-Myers Squibb and Gilead Sciences deliver stellar HCV results, decide to go separate ways?

Gilead claims that its decision to focus on internal developments, rather than partnering with Bristol-Myers Squibb has accelerated the development of its own efforts to bring a single tablet, interferon-sparing treatment to market. Gilead remains the leading player in this development race, albeit if its own impressive-looking combinations have yet to fully match the efficacy seen with sofosbuvir/daclastasvir, which are regarded as the best in class nucleotide NS5B inhibitor and NS5A inhibitor products, respectively.

With different assets in the HCV development space offering various mechanisms of action, mechanism diversity and potency, one suggestion is that once individual components become available, physicians will prescribe them together in an off-label capacity. In this respect, the HIV market – where combinations of best-in-class molecules are used despite different companies owning them – could prove to be a valid benchmark. Key opinion leaders (KOLs) suggest that such activity is likely to occur in the early period following the approval of new treatments, with off-label use also likely to be driven by independently-run clinical trials looking at cross-company regimens. See KOL Insight: Hepatitis C: the race for the first interferon-free regimen

Potential off-label use will have a direct impact on how companies price their own fixed-dose combinations, note KOLs, while the broader cost of treating an expanding HCV population will in turn limit the use of off-label prescribing, they add – particularly as Gilead, for example, has shown robust data for its own combination. One KOL told FirstWord that "there are just too many patients out there and the system could go bankrupt if screening and diagnosis rate of hepatitis C go up and everybody is just put on just a combination of the best drug classes. You may have people prescribing daclatasvir, simeprevir plus sofosbuvir, three drugs off label in a combination just because they feel that is really the best they can provide to their patients, but which from a healthcare perspective would be a disaster."

Source

Also See:

  1. HCV Combo Impresses, but Use Unlikely (April 30, 2013)
  2. Shunned Gilead/Bristol-Myers hep C combo may be too good for docs to ignore (April 28, 2013)
  3. Gilead-Bristol Hepatitis C Drug Combo Cures All in Study (April 28, 2013)
  4. Gilead-Bristol Hepatitis C Combo Cures 100% of Patients in Study (April 27, 2013)

FDA Rejects Two Gilead HIV Drugs as Standalone Products

Apr 29, 2013

By Toni Clarke

WASHINGTON (Reuters) Apr 29 - Gilead Sciences Inc said on Monday that U.S. health regulators rejected two of its HIV drugs as standalone therapies, citing deficiencies in documentation and validation of certain quality testing procedures.

The company is seeking approval for its integrase inhibitor elvitegravir for people with HIV who have already been treated with other products.

Gilead is also seeking approval of cobicistat, a drug that does not itself fight the virus but boosts the function of other HIV medicines.

Both drugs are already contained in Gilead's once-daily single-tablet HIV treatment Stribild, which combines four different medications and was approved in the United States last August.

Stribild contains elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate.

Gilead said it is working with the U.S. Food and Drug Administration to address the questions raised in the rejection letter in order to move the application forward.

Source

Benjamin Young, MD, PhD

Apr 30, 2013

Advances in antiretroviral medications have revolutionized the care and prognosis of people living with HIV around the world. Where individuals have access to trained care providers and medications, HIV-related morbidity and mortality have decreased; in many highly affected regions, new infection rates are beginning to decrease.

Yet, as impressive as these gains seem, recent studies show that only a minority of people living with HIV in the United States are successfully engaged in care and achieve viral suppression.[1,2] Central problems in HIV care are related to delays in testing, delays in care, and early dropout from medical care, and late access to HIV testing and treatment have been associated with increased immune system damage, risk for HIV transmission, and increased hospitalizations.[3]

Unfortunately, these seemingly obvious barriers to successful implementation of therapeutics have only recently drawn systematic attention. Improving engagement in HIV medical care is hobbled by a relative dearth of scientific literature on the vast subject. In appreciating such challenges, our group, the International Association of Providers in AIDS Care (IAPAC), convened an international expert panel to identify best practices and evidence for engagement and adherence to HIV care and treatment. These first-ever evidence-based recommendations on improving entry into and retention in HIV care and treatment adherence were published in 2012.[4]

In the current issue of JIAPAC, we describe a clinical management algorithm based on the evidence-based recommendations that charts simple operational interventions for engagement and care and treatment adherence. We believe that such tools can assist busy care programs in improving the delivery of important health interventions.

The algorithm recommends:

  • Systematic monitoring of successful entry into and retention in HIV care; multiple data sources may need to be integrated to best achieve this monitoring goal. Intensive outreach is recommended for recently diagnosed individuals who do not enter care within 6 months of diagnosis. Peers or paraprofessionals may be considered to provide the needed human resources to achieve these goals.
  • The use of once-daily treatment for persons initiating therapy. Among regimens of equal efficacy and safety, fixed-dose combinations should be used to decrease pill burden.
  • Monitoring of adherence to treatment by routine self-reported adherence and pharmacy refill data. Reminder devices and the use of communications technologies with an interactive component and adherence-related educations and counseling are recommended.
  • Education and counseling through one-on-one and group education; multidisciplinary education and counseling are recommended.
  • It is important to note that although normative guidance is a necessary step in charting a pathway for improving care, recommendations frequently are not translated into operational improvements. Indeed, it is critical that agencies that author such documents take into consideration the operational and educational needs of implementation.

As a member-oriented organization, IAPAC strives to provide practical tools to assist front-line care providers in achieving the highest possible level of care in people living with HIV. In the past, efforts have focused primarily on the use of HIV treatment guidelines from the US Department of Health and Human Services and the World Health Organization. In constructing and publishing this algorithm, we extend this effort to improving engagement in care and treatment adherence.

References

Source

April 30, 2013

Treatment-naive patients with chronic hepatitis C experienced high rates of sustained virologic response from a combination of three direct-acting antivirals in a study presented at the International Liver Congress in Amsterdam.

In an open-label phase 2 study, researchers randomly assigned 32 treatment-naive patients with chronic HCV genotype 1 to 60 mg NS5A inhibitor daclatasvir (DCV) once daily, 200 mg protease inhibitor asunaprevir (ASV) twice daily and 75 mg non-nucleoside NS5B inhibitor BMS-791325 twice a day for 24 or 12 weeks (n=16 each). A second cohort was later assigned DCV, ASV and 150 mg BMS-791325 (Bristol-Myers Squibb) for 24 (n=16) or 12 weeks (n=18).

Nearly all patients had HCV RNA levels below 25 IU/mL after 4 weeks, excluding two participants from the 12-week, 150-mg group. No significant differences in virologic response were observed, with 92% of all evaluable patients experiencing SVR at 4 weeks. SVR12 and SVR24 were achieved by 94% of the first two groups, and all evaluable patients in this cohort experienced either or both SVR24 and SVR36, according to a press release.

In the second cohort, three treatment failures occurred, including virologic breakthroughs in the 12- and 24-week groups and one relapse in the 12-week group.

The most commonly reported adverse event was headache (27.3% of cases). Single cases of renal calculus and cerebral vasoconstriction unrelated to the study were considered serious adverse events, but no patients died or discontinued therapy because of treatment-related effects.

“The diversity of the hepatitis C patient population requires multiple treatment options that can enable a personalized approach,” Brian Daniels, MD, senior vice president of Global Development and Medical Affairs for Bristol-Myers Squibb, said in the release. “These data, which demonstrate comparable efficacy among the 12- and 24-week triple-DAA treatment groups, support the rapid phase 3 development of this investigational triple-DAA regimen and provide further data on daclatasvir as an important component of DAA-based therapy.”

For more information:

Everson GT. #1423: Interim Analysis of an Interferon (IFN)- and Ribavirin (RBV)-Free Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 in Treatment-Naive, Hepatitis C Virus Genotype 1-Infected Patients. Presented at: The International Liver Congress 2013; April 24-28, Amsterdam.

Source

April 30, 2013

Heavy alcohol consumption and obesity increase the risk for liver-related morbidity and death, while metabolic risk factors also elevate the risk for hepatocellular carcinoma, according to data presented at the International Liver Congress in Amsterdam.

In a study of 107,742 women (median age 60 years) stratified according to BMI (less than 25 kg/m2 vs. 25 kg/m2 or more) and alcohol intake (15 units or fewer consumed weekly vs. more than 15), researchers observed 90 incidents of morbidity or mortality related to liver disease. Patients with high BMI and alcohol intake were at significantly increased risk (HR=7.2; 95% CI, 3.4-15.5) compared with those with low BMI and low alcohol consumption, while the association also neared statistical significance among those with low BMI and high alcohol intake (HR=2.9; 95% CI 1.0-8.4).

“These findings will have a significant impact on how we can help millions of people across the world at risk of developing liver disease,” Daniele Prati, MD, EASL Scientific Committee Member, said in a press release. “More research is required to determine the exact thresholds for each risk factor that independently and in combination increase the risk of chronic liver disease, but this is an important first step in the right direction.”

In another study presented at the congress, investigators evaluated 100 liver transplant recipients with alcoholic cirrhosis, including 24 with steatosis, 24 with metabolic risk factors such as obesity and/or diabetes (MRF), 20 with both and 32 with neither steatosis nor MRF.

Hepatocellular carcinoma (HCC) was present in 28 patients, who were significantly more likely to be overweight (54% of cases vs. 14%; P<.001) and have diabetes (43% vs. 22%; P<.04) than those without HCC. Half of participants with both steatosis and MRF had HCC, compared with 6% of those with neither. Significantly more patients in either the MRF/steatosis combined or MRF alone groups had HCC than those with neither or steatosis alone (48% vs. 13%; P=.0001). Adjustment for factors including age, sex and alcohol consumption did not eliminate the associations between HCC and obesity (P<.01) or diabetes (P<.04).

“Fatty liver and alcohol have long been known as risk factors for HCC, but this study tested their combined effect in patients with alcoholic cirrhosis,” Prati said in the release. “The results will be useful to improve the management of patients with cirrhosis, and to identify cancer at early stages.”

For more information:

Trembling PM. #115: Influence of BMI and Alcohol on Liver-Related Morbidity and Mortality in a Cohort of 108,000 Women From the General Population From UKCTOCS. Presented at: The International Liver Congress 2013; April 24-28, Amsterdam.

Pais R. #118: Metabolic Fatty-Liver Disease Increases the Risk of Hepatocellular Carcinoma in Patients With Alcoholic Cirrhosis Listed for Liver Transplantation. Presented at: The International Liver Congress 2013; April 24-28, Amsterdam.

Source

HCV Combo Impresses, but Use Unlikely

By Michael Smith, North American Correspondent, MedPage Today

Published: April 30, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

Action Points

  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • This phase II trial demonstrated a nearly 100% sustained virologic response rate with the use of daclatasvir and sofosbuvir in patients with hepatitis C virus infection refractory to standard therapy.
  • Unfortunately, the two drugs are made by different companies and will not be marketed together, making phase III trials difficult.

AMSTERDAM -- Researchers and clinicians got another look here at a combination of investigational oral hepatitis C virus (HCV) drugs that delivered impressive results but will likely never be marketed together.

In a small phase II cohort of very difficult-to-treat patients, the combination of sofosbuvir and daclatasvir led to viral cures in 40 of 41 patients 12 weeks after the end of therapy, according to Mark Sulkowski, MD, of Johns Hopkins University.

The 41st patient did not appear to be tested at week 12 and so was counted as a treatment failure, but was tested 24 weeks after the end of therapy and found to have unquantifiable levels of HCV RNA, Sulkowski reported at the meeting of the European Association for the Study of the Liver.

He added that of the 21 patients who have completed 24 weeks of follow-up after treatment, all have undetectable virus – the so-called 24-week sustained virologic response (SVR24).

In addition, the combination was well-tolerated with few adverse events, and no patient has yet relapsed, he said.

In other words, the all-oral, once-daily combination "looks exceedingly useful," commented Geoffrey Dusheiko, MD, of Royal Free Hospital in London, who was not involved with the study but who moderated the session at which it was presented.

But the combination is running afoul of diverging corporate interests, he noted. Daclatasvir, an NS5A replication complex inhibitor, is owned by Bristol-Myers Squibb, while sofosbuvir, a nucleotide analogue NS5B polymerase inhibitor, is being developed by Gilead Sciences.

The companies have stopped collaborating on the drugs, with each firm preferring to develop its own version of the other's medication.

The result, Dusheiko said, is that "we don't have a large body of phase III data and that may restrict physicians from prescribing this particular combination."

"Unless there's a change in the thinking," he said, it's unlikely the companies will get back together, adding that for clinicians, "It's a conundrum."

Sulkowski reported on 41 patients with the hard-to-treat genotype 1 of the virus who had failed treatment with the current standard of care: a protease inhibitor -- either telaprevir (Incivek) or boceprevir (Victrelis) -- combined with pegylated interferon and ribavirin.

Such patients have no treatment options, Sulkowski said. He and colleagues randomly assigned the 41 volunteers to take sofosbuvir and daclatasvir alone or with ribavirin for 24 weeks. The primary endpoint of the analysis was unquantifiable HCV RNA 12 weeks after the end of therapy – the so-called SVR12.

All patients but one had unfavorable variants of the IL28B gene, which predicts response to interferon treatment, and 33 of 41 had HCV genotype 1a, which is regarded as more difficult to treat than 1b.

Nevertheless, Sulkowski reported, high response rates were seen early in treatment and by the end of therapy all 41 patients had unquantifiable virus, a state that persisted (with the one technical exception) through 12 weeks post-treatment.

There were no serious adverse events in patients taking the combination alone, no discontinuations owing to adverse events, and no grade 3 or 4 adverse events.

In the other arm, the combination plus ribavirin was nearly as well-tolerated with one serious adverse event – a single patient with hypokalemia.

Adverse events reported by at least 10% of patients included fatigue, headache, hair loss, muscle aches, constipation, and diarrhea, Sulkowski said, but all were mild or moderate.

The study had support from Gilead and Bristol-Myers Squibb. Sulkowski reported financial links with the company, as well as with Novartis, BMS, Gilead, Janssen, Vertex, BIPI, Abbott, Merck, Roche/Genentech, BIPI, and Pfizer.

Dusheiko reported financial links with Gilead, GSK, BMS, and Boehringer Ingelheim.

Primary source: European Association for the Study of the Liver
Source reference:
Sulkowski MS, et al "Sustained virologic response with daclatasvir plus sofosbuvir ± ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC)" EASL 2013; Abstract 1417.

Source

Also See:

  1. Shunned Gilead/Bristol-Myers hep C combo may be too good for docs to ignore (April 28, 2013)
  2. Gilead-Bristol Hepatitis C Drug Combo Cures All in Study (April 28, 2013)
  3. Gilead-Bristol Hepatitis C Combo Cures 100% of Patients in Study (April 27, 2013)

PRESS RELEASE

* Reuters is not responsible for the content in this press release.

Tue Apr 30, 2013 11:45am EDT

GENFIT: GFT505 AT THE HEART OF POTENTIAL THERAPIES DURING THE ANNUAL EASL CONGRESS

Lille (France), Boston (Massachusetts, United States), April 30, 2013 - GENFIT (Alternext: ALGFT; ISIN: FR0004163111), a biopharmaceutical company at the forefront of drug discovery and development, focusing on the early diagnosis and preventive treatment of cardiometabolic and associated disorders, today announces that NASH was a prominent theme at the international liver congress of EASL held in Amsterdam, and that GFT505 is indisputably recognized as one of the most promising drug candidates in this indication.

NAFLD and NASH is a major preoccupation of experts in hepatology. As such, these liver disorders associated with conditions such as obesity and type 2 diabetes mellitus, were the subject of over 50 scientific communications during the EASL congress, underlining in particular the morbidities and increasing prevalence, not only in industrialized but also emerging countries. During a state-of-the-art session entitled "NAFLD 2013: a clinical update", Pr. Christopher Day clearly provided the latest results on epidemiology, pathophysiological processes, and natural history of the disease, which pointedly put forward the urgent need for new therapies. In this context, Pr. Day considered the mechanism of action of GFT505 as a promising approach presently in clinical evaluation for NASH.

In addition to the conference of Pr. Day, other communications were presented on GFT505 as an excellent drug candidate for the treatment of NASH. Notedly, in his presentation entitled « An overview of lipotoxicity by nuclear receptors », Pr. Bart Staels detailed the roles of nuclear receptors PPARa and PPARd, targets of GFT505, in the mechanisms associated with NASH. Based on these known mechanisms, Pr. Staels presented the latest preclinical and clinical results demonstrating the efficacy of GFT505, and indicated that these new findings have been accepted for publication in major international peer reviewed scientific journals (Hepatology and Diabetes Care). Their official publications will be announced in the coming weeks.

The important satellite meeting organized by GENFIT, which gathered together over 90 clinical investigators and key opinion leaders from different countries implicated in the GFT505-212-7 study, provided confirmation of the acute interest which the scientific community has on GFT505 as a treatment of NASH. The investigators noted in particular the exceptional efficiency of patient recruitment in the study, which demonstrates the hope and anticipation incited by GFT505 in NASH patients who today are without any therapeutic solution.

*About NAFLD/NASH:
NAFLD (non-alcoholic fatty liver disease) and in particular NASH (non-alcoholic steatohepatitis) are serious liver diseases that can lead to cirrhosis and liver cancer. The development of NAFLD/NASH is associated with the pathophysiological process of insulin resistance in patients that are overweight and/or diabetic. NAFLD is believed to affect 70-80% of diabetic patients, and progresses to chronic liver disease (NASH) in 20-50% of cases. Mortality due to liver disease is thus 2-3-fold higher in the diabetic population than in the overall population. The NASH market was estimated at 615 $M in 2010 and should reach 2,008 $M in 2018.

About GENFIT:

GENFIT is a biopharmaceutical company focused on the Discovery and Development of drug candidates in therapeutic fields linked to cardiometabolic disorders (prediabetes/diabetes, atherosclerosis, dyslipidemia, inflammatory diseases.). GENFIT uses a multi-pronged approach based on early diagnosis, preventive solutions, and therapeutic treatments and advances therapeutic research programs, either independently or in partnership with leading pharmaceutical companies, including Sanofi, to address these major public health concerns and their unmet medical needs.
GENFIT's research programs have resulted in the creation of a rich and diversified pipeline of drug candidates at different stages of development, including GENFIT's lead proprietary compound, GFT505, that is currently in Phase IIb.
With facilities in Lille, France, and Cambridge, MA (USA), the Company has approximately 80 employees. GENFIT is a public company listed on the Alternext trading market by Euronext(TM) Paris (Alternext: ALGFT; ISIN: FR0004163111). www.genfit.com

Contacts:

GENFIT
Jean-François Mouney - CEO & Chairman of the Management Board
Ph. +333 2016 4000

Milestones - Press Relations
Bruno Arabian
Ph. +331 7544 8740 / +336 8788 4726 - barabian@milestones.fr

2013.04.30 PR GENFIT EASL

Source

PR-Logo-GlobeNewswire

PRESS RELEASE

April 30, 2013, 8:02 a.m. EDT

 

Data Support Unmet Therapeutic Need in Primary Biliary Cirrhosis and Strong Statistical Correlation of POISE Phase 3 Primary Endpoint With Clinical Outcomes

NEW YORK, April 30, Apr 30, 2013 (GLOBE NEWSWIRE via COMTEX) -- Intercept Pharmaceuticals, Inc. /quotes/zigman/12230574/quotes/nls/icpt ICPT -0.09% , a clinical stage biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat chronic liver diseases, today announced additional details relating to the analysis presented by the Global Primary Biliary Cirrhosis Study Group (Study Group) at the annual meeting of the European Association for the Study of the Liver (EASL) held in Amsterdam on April 24-28, 2013. The Study Group presented an analysis of data from over 2,100 primary biliary cirrhosis (PBC) patients, among whom 981 patients met Intercept's ongoing Phase 3 POISE trial entry criteria at the time they initiated ursodiol therapy of having an alkaline phosphatase (ALP) level exceeding 1.67 times upper limit normal (ULN) and/or an abnormal bilirubin level. The analysis of this cohort of patients from the Study Group further substantiates the primary endpoint used in POISE as being strongly predictive of adverse clinical outcomes such as liver transplant and death in PBC patients.

"This independent analysis from the Study Group further validates the use of a surrogate endpoint in PBC trials to predict long-term outcomes," said Mark Pruzanski, M.D., Chief Executive Officer and President of Intercept. "Our selection of the POISE trial endpoint was based on a recent emerging consensus of leading PBC opinion leaders and we are glad to see that the Study Group data analyzed to date support its clinical utility."

The data show that after one year of ursodiol therapy 58.7% of the patient cohort (n=576/981) had an inadequate therapeutic response as determined by failure to meet the POISE trial primary endpoint, which is defined as the achievement of both an ALP level of less than 1.67 times ULN (with a minimum 15% reduction from baseline) together with a normal bilirubin level. In the non-responder group, 30.0% of patients went on to require a liver transplant or die (n=173/576) as compared to 12.6% of patients in the responder group (n=51/405), reflecting a 2.4-fold higher event rate for the non-responders (p=4.5x10E-10).

In order to censor out deaths due to causes other than PBC-associated liver failure, the Study Group, among other things, analyzed a younger subgroup of patients who were under 60 years old (n=666) at the time they initiated ursodiol therapy. In this subgroup, 61.3% of patients (n=408/666) failed to meet the POISE endpoint after one year of ursodiol therapy and 26.2% of these patients went on to require a liver transplant or die (n=107/408), as compared to 7.4% of patients in the responder group (n=19/258), reflecting a 3.6-fold higher event rate for the non-responders (p=1x10E-7).

The event rate among the responders in this subgroup was 41.3% lower than the event rate of the responder group in the overall patient cohort that included older patients. We believe that this difference is likely due to the greater exclusion of mortality unrelated to PBC in the younger patient subgroups, resulting in even greater differentiation of the responder and non-responder groups.

About The Global Primary Biliary Cirrhosis Study Group

The Global Primary Biliary Cirrhosis Study Group is currently comprised of a group of 15 academic medical centers from eight countries that are pooling their data to investigate the relationship between biochemical assessments of liver function and adverse clinical outcomes in primary biliary cirrhosis. Intercept is sponsoring this independent academic research program but is not involved in the data collection and analysis, which are being conducted by Dr. Henk van Buuren and Dr. Bettina Hansen of Erasmus University Medical Centre in Rotterdam, The Netherlands. The data demonstrate that the primary endpoint being used in Intercept's Phase 3 POISE trial is highly statistically predictive of liver transplant-free survival in primary biliary cirrhosis patients. Intercept anticipates final data from at least 4,000 patients will be collected and analyzed as part of the study.

About Obeticholic Acid (OCA) and the POISE Trial

Intercept's lead product candidate, obeticholic acid, is a bile acid analog and first-in-class agonist of the farnesoid X receptor (FXR). OCA is initially being developed for the second line treatment of primary biliary cirrhosis in patients with an inadequate response to, or who are unable to tolerate, ursodiol (ursodeoxycholic acid), the only approved therapy for this indication. Primary biliary cirrhosis is a chronic autoimmune liver disease that may progress to cirrhosis and liver failure, and it is currently the fifth leading indication for liver transplant in the United States. Intercept is currently conducting a Phase 3 clinical trial of OCA in primary biliary cirrhosis, called the POISE trial, which is anticipated to serve as the basis for seeking regulatory approval in the United States and Europe. Intercept completed enrollment of 217 patients in the POISE trial in December 2012 and expects results to be available in the second quarter of 2014. OCA has orphan drug designation in both the United States and Europe for the treatment of PBC. Intercept owns worldwide rights to OCA outside of Japan and China, where it has out-licensed the product candidate to Dainippon Sumitomo Pharma.

About Intercept

Intercept is a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat orphan and more prevalent liver diseases utilizing its expertise in bile acid chemistry. For more information about Intercept, please visit the Company's website at www.interceptpharma.com.

Safe Harbor Statement

This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the relationship between ALP and bilirubin and adverse clinical outcomes, the clinical utility of the POISE trial selected endpoints and any potential consensus relating thereto, the acceptance by regulatory authorities of the POISE trial endpoint or results, clinical, preclinical and regulatory developments for our product candidates, the anticipated results of our clinical and preclinical trials and other development activities, and our strategic directives under the caption "About Intercept." These "forward-looking statements" are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: the initiation, cost, timing, progress and results of Intercept's development activities, preclinical studies and clinical trials; the timing of and Intercept's ability to obtain and maintain regulatory approval of OCA and any other product candidates it may develop, and any related restrictions, limitations, and/or warnings in the label of any approved product candidates; Intercept's plans to research, develop and commercialize future product candidates; the election by Intercept's collaborators to pursue research, development and commercialization activities; Intercept's ability to attract collaborators with development, regulatory and commercialization expertise; Intercept's ability to obtain and maintain intellectual property protection for its product candidates; Intercept's ability to successfully commercialize its product candidates; the size and growth of the markets for Intercept's product candidates and its ability to serve those markets; the rate and degree of market acceptance of any future products; the success of competing drugs that are or become available; regulatory developments in the United States and other countries; the performance of third-party suppliers and manufacturers; Intercept's ability to obtain additional financing; Intercept's use of the proceeds from its recently completed initial public offering; the accuracy of Intercept's estimates regarding expenses, future revenues, capital requirements and the need for additional financing; the loss of key scientific or management personnel; and other factors discussed under the heading "Risk Factors" contained in Intercept's annual report on Form 10-K for the year ended 2012 filed with the Securities and Exchange Commission on April 1, 2013, as well as any updates to these risk factors filed from time to time in Intercept's other filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Intercept undertakes no duty to update this information unless required by law.

For more information about Intercept, please contact Mark Pruzanski, M.D., or Barbara Duncan, both of Intercept Pharmaceuticals, at 1-646-747-1000.

http://www.globenewswire.com/newsroom/ti?nf=MTMjMTAwMzA1NjcjMjMwMjQ=

Source

April 29, 2013

The Diagnosis and Treatment of Hepatitis C: A Technical Landscape

Opportunities to Revolutionise Care in Developing Countries

This report provides an overview on the current state of play and a framework for action with regards to hepatitis C diagnostics and treatment in resource-poor settings.

SUMMARY AND STATEMENT OF PRIORITY

Hepatitis C (HCV) has been a silent killer among people living in low- and middle-income countries. Factors including lack of epidemiologic data, poorly tolerated treatment with low success rates, and cost and complexity of care have all contributed to a vicious cycle of neglect that has allowed a growing epidemic of HCV to blossom unchecked.

But recent advances in both diagnosis and treatment, as well as new data on prevalence in low- and middle-income countries, provides an unprecedented opportunity to take the lead in turning back the growing tide of HCV and dramatically improve the wellbeing of people infected with HCV. New all-oral regimens offer the potential of being robust, well-tolerated and pan-genotypic.

Thus, not only improving cure rates, but also simplifying diagnosis and management requirements. Advances in and scale up of molecular testing in low-resource environments facilitates diagnosis and monitoring of HCV.

Taken together, these new tools open the door to managing this deadly coinfection in low- and middle-income countries. The simplified package of care may also enable decentralization of diagnosis and treatment as well as pave the way for eventual task-shifting to less specialized cadres of health workers. However, several key interventions are required in order to spark this revolution in HCV care:

• Proactive normative guidelines at the WHO and at country level are needed
• Regular screening of patients at high risk for HCV, including those infected with HIV, is critical
• Access to appropriate diagnostics, including molecular tests, is of utmost importance and can be facilitated by utilizing the same platforms currently being rolled out for HIV
• Prices of both interferon-based therapy as well as new all-oral therapy must be appropriate to facilitate scale up in low- and middle-income countries, and biosimilar and generic competition is required in order to reach a fair price.
• Access to new oral therapies depends not only on price but also on registering of these new medications in key countries, as well as the WHO or other normative bodies signaling their importance by inclusion in the model Essential Medicines List.

There is no time like the present to rapidly address this hidden and ignored epidemic. The benefits of new tools and data will not be realised without key market interventions as well as prioritisation of this disease at the WHO and at country level. But if the choice is made to invest now in the tools needed to fight HCV in low- and middle-income countries, the potential benefits are vast.

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Task force calls for routine HIV testing for all adults

By Julie Steenhuysen

CHICAGO | Tue Apr 30, 2013 2:41am IST

CHICAGO (Reuters) - An influential panel is calling for HIV screening for all Americans aged 15 to 65, regardless of whether they are considered to be at high risk, a change that may help lift some of the stigma associated with HIV testing.

The new guidelines from the Preventive Services Task Force (USPSTF), a government-backed panel of doctors and scientists, now align with longstanding recommendations by the Centers for Disease Control and Prevention for testing of all adults aged 15 to 65, regardless of their risk.

Prior guidelines issued by the USPSTF in 2005 had recommended HIV screening for high-risk individuals.

Experts said the guideline change, published on Monday in the Annals of Internal Medicine, will likely trigger coverage for the tests as a preventive service under the Affordable Care Act. Under President Barack Obama's healthcare law, insurers are required to cover preventive services that are recommended by the task force.

Currently, the healthcare law recommends coverage of HIV testing for adolescents and adults who are at higher risk of infection.

"That was based on the 2005 USPSTF recommendations," Dr. Jeffrey Lennox, a professor of medicine at Emory University School of Medicine and chief of infectious disease at Grady Memorial Hospital, an inner-city hospital in Atlanta.

"Now, hopefully they will go back and re-categorize that and recommend that it will be covered for every adult."

A spokeswoman for the U.S. Department of Health and Human Services could not confirm the tests would be covered, but Lennox said it may take a while before the agency catches up to the new policy.

(Reporting by Julie Steenhuysen; Editing by Douglas Royalty)

Source

Journal of Viral Hepatitis

R. Firdaus, K. Saha, P. C. Sadhukhan

J Viral Hepat. 2013;20(4):290-293.

Abstract and Introduction
Abstract

Rapid testing for HCV has become a routine practice in resource-limited settings for initial screening. The objective of this study was to evaluate the performance of rapid immunoassay diagnostic test kits for specific and accurate diagnosis of HCV infection among different patient groups in clinical settings of Kolkata, India. Two hundred and fifty-four randomly selected serum samples of 612 samples reported as HCV nonreactive by rapid immunodiagnostic tests were evaluated for HCV antibody, ELISA and HCV RNA testing for confirmatory diagnosis. 15.74% were HCV seropositive by ELISA, and 11.02% were RNA positive by nested RT-PCR. Additionally, 15 HCV-seronegative chronic liver disease patients with high ALT and AST values were screened for HCV RNA, of which five were positive whose viral load ranged from 1.2 × 102 to 4.4 × 106 IU/mL, and the samples belonged to IVDUs and HIV-co-infected individuals. The results showed that HCV rapid immunoassay test cannot be solely relied on as an absolute and accurate diagnostic tool for screening infection of HCV particularly in high-risk group patients such as IVDUs, haemodialysis, thalassaemic and HIV-co-infected patients who need HCV screening frequently.

Introduction

Hepatitis C virus (HCV) infection is a global health problem affecting around 170 million people worldwide and is a leading cause of liver cirrhosis and hepatocellular carcinoma.[1] In India, HCV infection as a cause of acute viral hepatitis has been reported to vary between 0–21% and responsible for 14–26% cases of chronic liver disease.[1] HCV infection is mostly acquired through transfusion of blood or blood products. A high prevalence of HCV is found in many high-risk groups (HRG) exposed to blood or blood products, like intravenous drug users (IVDUs), patients with paediatric haematologic malignancies and those with thalassaemia and haemophilia. The prevalence of HCV in blood donors in India (1–1.5%) is higher than that in developed countries.[2]

The laboratory diagnosis of HCV infection is based on the detection of circulating antibodies and viral RNA. The most widely used HCV screening tests are ELISA and HCV RNA by nucleic acid test (NAT), as they are the most appropriate for screening large numbers of specimens on a daily basis.[3] These assays are technically demanding and require sophisticated laboratory infrastructure. Hence, in developing countries like India, the blood transfusion centres mostly rely on simple, rapid tests for HCV with individual kits as an inexpensive alternative for ELISA or NAT assays. Although the use of simple rapid immunoassays has significantly reduced the risk of HCV transmission, the window period for the detection of recent or new infection among the high-risk group remains a concern. The purpose of our study was to determine the performance of simple rapid immunoassay in patients who belonged to high-risk group such as thalassaemic and haemodialysis patients, who undergo blood transfusions regularly. As no previous literature is available on the contradictory results of the HCV rapid immunoassay, our study aimed to help the clinicians and the laboratory personnel on false-negative results of the rapid immunoassay, so that in future more confirmatory screening tests would be employed in blood transfusion centres to detect accurately the status of the HCV-positive patients.

Material and Methods
Clinical Samples

Blood samples were collected from different liver clinics, haemodialysis centres, HIV Apex Clinic and thalassaemic patients from Kolkata between March 2006 and February 2011. Among the 612 samples received during this period, 254 samples that were hepatitis B and HCV rapid immunoassay nonreactive but having increased levels of AST and ALT in patients with chronic liver diseases were included in this study. This was an IEC-approved study, and informed consent was obtained from the individuals during the collection of blood samples.

Detection of HCV Antibody by Rapid Immunoassay and ELISA

Rapid diagnosis of HCV was performed using fourth-generation HCV TRI-DOT (WHO-GMP certified, sensitivity 100% and specificity 98.9%; J. Mitra, New Delhi, India), as well as with Signal HCV Kit (sensitivity 98% and specificity 99.45%; Span Diagnostics Ltd, Surat, India).[4] The same sets of samples were tested for the presence of antibodies against HCV core, NS3 and NS5 regions using two commercially available ELISA kits Hepanostika anti-HCV Ultra Kit (Biomerieux, Boxtel, The Netherlands) and HCV Microlisa (J. Mitra) to verify the results. The fourth-generation HCV TRI-DOT utilizes a unique combination of modified HCV antigens conserved across all genotypes from the putative core, NS3, NS4 and NS5 regions of the virus to selectively identify all genotypes of HCV in human serum/plasma with a high degree of sensitivity and specificity.

Detection and Quantitative Estimation of HCV RNA

The viral RNA was extracted using QIAamp viral RNA mini kit (QIAGEN, Hilden, Germany) according to the manufacturer's protocol. HCV viral RNA was detected by nested RT-PCR based on 5' noncoding region (5' NCR) of HCV genome according to Saha et al..[5] Briefly, the first-round RT-PCR was performed in 20-μL total reaction volume containing 2 μL of isolated RNA with outer forward primer (PS1) 5'-ACTGTCTTCACGCAGAAAGCGTCTAGCCAT-3' and outer reverse primer (PA1) 5'-CGAGACCTCCCGGGGCACTCGCAAGCACCC-3'. The second-round nested PCR was performed with inner forward primer (PS2) 5'-ACGCAGAAAGCGTCTAGCCATGGCGTTAGT-3' and inner reverse primer (PA2) 5'-TCCCGGGGCACTCGCAAGCACCCTATCAGG-3'. The primers were selected/used in this nested RT-PCR from highly conserved domains within the 5' NCR region of the HCV genome according to Bukh et al.,[6] which is well conserved across all the six HCV genotypes. A positive band at 256 bp in 1.5% agarose gel stained with ethidium bromide was observed in gel documentation system (Bio-Rad Laboratories, Hercules, CA, USA) for HCV RNA-positive samples. Quantitative hepatitis C viral RNA was determined using ABI real time RT-PCR kit (AgPath-IDTM One-Step RT-PCR kit, Applied Biosystems, Foster City, CA, USA). The HCV primer and probe sequences were directed against the 5' noncoding region of the HCV genome.

DNA Sequencing and Genotyping

Nested RT-PCR-amplified 256-bp amplicon of 5' NCR of HCV genome was gel-purified and directly used for DNA sequencing analysis in an automated DNA Sequencer, model 3130XL (Applied Biosystems) using Big Dye terminator 3.1 kit (Applied Biosystems). The genotypes of the sequences obtained were determined using the NCBI genotyping tool.[7]

Statistical Analysis

Mean and median values were calculated. The P-values ≤ 0.05 were considered statistically significant.

Results and Discussion

The study involved 612 patients who were screened for HCV infection using rapid immunoassay kits. Seventy-nine per cent of the patients belonged to 40–60 age group, of which 74% of the patients were men and 26% women.

All serum samples selected in this study were evaluated using two different rapid HCV immunodetection kits, namely TRI-DOT and Signal HCV. Of the total 612 samples, 254 (41.50%) reported as HCV nonreactive were screened for this study. Furthermore, of the 254 samples, 40 (15.74%) were seroreactive by both the ELISA methods. All the seropositive samples were screened for HCV RNA detection; among them, 28 (70%) were HCV RNA positive.

Fifteen-ELISA-nonreactive samples from HRG with a history of chronic liver disease and high AST and ALT values were processed for HCV RNA detection. Five samples were HCV RNA positive, of which three were IVDUs and other two were HIV-co-infected patients with a history of surgery and blood transfusion (). All these HCV RNA-positive samples were further processed for viral quantitation and genotyping. It was found that the viral load ranged from 1.2 × 102 to 4.4 × 106 IU/mL and four were genotype 3, whereas one was genotype 1 (). The median ALT value was calculated at 45 IU/mL (min. 15.55, max. 111.32 IU/mL) and AST at 109.63 IU/mL, respectively (min. 60.23, max. 293.36 IU/mL) (Table 1).

From our results, we could surmise that HCV rapid immunoassay gave false-negative results in patients belonging to high-risk group especially in IVDUs, haemodialysis, thalassaemic, and HIV-co-infected patients. 11.02% of samples marked as rapid immunoassay nonreactive were in fact HCV RNA positive as determined by NAT (HCV RNA) assays. Results obtained were compared by additionally testing the samples using ELISAs and NAT. Two different ELISA kits were used to compare the specificity of the results. Forty (15.74%) samples were seropositive by both the HCV ELISA kits. In addition, the findings showed that of 15 ELISA-seronegative samples, five were HCV RNA positive, that is, the patients were active carriers of the HCV infection. All the seronegative samples that were HCV RNA positive belonged to patients in high-risk group. One of the striking observations was that even though these patients were asymptomatic and declared as HCV nonreactive by rapid immunoassay, they had high levels of ALT and AST values that indicated a dysfunction in their liver.

Our genotyping data showed that of the HCV RNA-positive patients, 80% were infected with genotype 3. The viral load in patients with genotype 3 was significantly lower than in those infected with genotype 1. Diagnosis of HCV in these cases is difficult, as these patients cannot produce sufficient anti-HCV antibodies because of immunosuppression.[8] Additionally, false-negative results could be attributed to genetic heterogeneity, which could affect the serological response. The most prevalent HCV strain in India is genotype 3,[9] which is a slow-growing variant, and therefore, the probability of false negatives for this genotype may increase in rapid immunoassay tests. Although HCV rapid immunoassays are routinely used in practically all laboratories, our results showed for the first time that many of the samples declared as HCV rapid immunoassay nonreactive in initial screening were in fact HCV RNA positive, that is, the patients were active carriers of the infection. This shows that rapid tests might give false-negative results particularly for patients belonging to HRG. Missing positivity in immunoassays occurs mainly in immunocompromised patients who fail to clear away the antigens or in patients with autoimmune disorders, hyperglobulinemia or in low-risk blood donors who donate blood frequently. In these cases, confirmatory HCV tests by nucleic acid amplification test (NAT) assays remain the method of choice. The presence of HCV RNA in a patient's serum confirms the active state of infection.

To conclude, the present study highlights that HCV rapid immunoassay tests should not relied upon as the sole criterion for screening patients in high-risk group. In these cases, confirmatory methods should be deployed for HCV detection, so that the rate of false-negative results can be scaled down, and the patients can be effectively screened and put on medication as soon as possible. Although this study is in a preliminary stage, it aims to provide useful inputs to scientific community and the policy makers to improve the existing infrastructure in screening patients for HCV.

References
  1. WHO. Global surveillance and control of hepatitis C. Report of a WHO Consultation organised with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat 1999; 6: 35–47.

  2. Jindal N, Arora U, Singh K. Prevalence of human immunodeficiency virus (HIV), Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) in three groups of populations at high risk of HIV infection in Amritsar (Punjab), Northern India. Jpn J Infect Dis 2008; 61: 79–81.

  3. WHO. Hepatitis C Assays: Operational Characteristics (Phase I) Report 1 January 2001.

  4. HCV TRI-DOT rapid visual test for the qualitative detection of antibodies to hepatitis C virus in human serum/plasma HCV antigens for Core, NS3, NS4 & NS5 protocol. Available at: http://jmitra.co.in/download/Procedure/Manual-HCV-Tri-Dot.pdf. (accessed 23 August 2012)

  5. Saha K, Firdaus R, Santra P et al. Recent pattern of co-infection amongst HIV seropositive individuals in Tertiary Care Hospital, Kolkata. Virol J 2011; 8: 116.

  6. Bukh J, Purcell RH, Miller RH. Importance of primer selection for the detection of hepatitis C virus RNA with the polymerase chain reaction assay. Proc Natl Acad Sci USA 1992; 89(1): 187–191.

  7. Rozanov M, Plikat U, Chappey C, Kochergin A, Tatusova T. A webbased genotyping resource for viral sequences. Nucleic Acids Res 2004; 32 (Suppl 2): W654–W659.

  8. Dalekos GN, Boumba DS, Katopodis K et al. Absence of HCV viraemia in anti HCV negative haemodialysis patients. Nephrol Dial Transplant 1998; 13: 1804–1806.

  9. Hissar SS, Goyal A, Kumar M et al. Hepatitis C virus genotype 3 predominates in North and Central India and is associated with significant histopathologic liver disease. J Med Virol 2006; 78(4): 452–458.

Source

Drug Trio Helps Treat HCV After Transplant

By Michael Smith, North American Correspondent, MedPage Today

Published: April 29, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM – Three-drug therapy appears to help liver transplant patients whose hepatitis C (HCV) recurs, a researcher said here.

In early results from an observational cohort, about two-thirds of evaluable patients had undetectable virus 4 weeks after the end of therapy with pegylated interferon and ribavirin along with a protease inhibitor, according to Elizabeth Verna, MD, of Columbia University in New York City.

But that must be "balanced" against a high rate of adverse events, including need for hospital admission, kidney dysfunction, and death, Verna reported at the meeting of the European Association for the Study of the Liver.

Treatment with pegylated interferon and ribavirin has been shown to lead to sustained virologic responses in about 30% of patients with the hard-to-treat genotype 1 of the virus, Verna noted.

And adding one of the recently approved protease inhibitors – telaprevir (Incivek) or boceprevir (Victrelis) – improves the odds, she said.

But triple therapy has not been tested in transplant patients whose genotype 1 virus recurs, usually in a very aggressive fashion. To help fill the gap, she and colleagues are following 112 patients receiving triple therapy at six U.S. centers.

Of those, she noted, 15 had been on pegylated interferon and ribavirin for more than 90 days before the protease inhibitors were approved in mid-2011 and they could be started on the new drugs.

Those patients were excluded from efficacy analyses, but included in safety studies.

The other 97 patients had a short lead-in period with interferon and ribavirin, followed by triple therapy (with telaprevir in most cases), and then took interferon and ribavirin again, for a total of 48 weeks.

Verna presented efficacy data at the EASL meeting on a subset of 43 patients who have completed therapy and had at least 4 weeks of observation afterward. Most remaining patients are still on interferon/ribavirin.

Verna said that 63% of those patients had what she called an extended rapid virologic response, defined as undetectable HCV viremia 4 and 12 weeks after the start of triple therapy.

At the end of therapy, 67% had undetectable viremia, and 4 weeks later the rate was 65%.

Currently, in the era of triple therapy and a host of investigational direct-acting HCV drugs, undetectable viremia 12 weeks after the end of therapy is regarded as tantamount to a cure.

While the early efficacy results are promising, Verna said 11% of the cohort had adverse events that led to stopping treatment, 21% needed to be admitted to hospital, 34% needed transfusions, 4% suffered graft rejection, and 6% died (4% from liver-related causes).

The study is an important step forward, although the results remain preliminary, commented Patrizia Burra, MD, PhD, of Padova University Hospital in Padua, Italy, who was not involved in the study but who moderated an EASL session at which it was presented.

At a minimum, the investigators have "demonstrated that [triple therapy] can be used quite safely," she told MedPage Today. She noted that high rates of adverse events are to be expected in these patients, many of whom have aggressive disease.

Also the preliminary efficacy data are encouraging, she said, and suggest it may be possible to rescue HCV patients who relapse after transplant. "We're really hoping to see good results," she said.

Neither Verna nor Burra reported any conflicts of interest.

Primary source: European Association for the Study of the Liver
Source reference:
Verna EC, et al "A multicenter study of protease inhibitor-triple therapy in hcv-infected liver transplant recipients: Report from the CRUSH-C group" EASL 2013; Abstract 23.

Source

'Quad' HCV Tx Works but No More Trials Planned

By Michael Smith, North American Correspondent, MedPage Today

Published: April 29, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM – A four-drug regimen was effective in hard-to-treat hepatitis C (HCV) patients who had previously failed therapy, a researcher said here, but the drug combination is not being further developed.

In a phase II study, 70% of patients had undetectable HCV virus 12 weeks after ending the so-called "quad regimen," according to Gregory Everson, MD, of the University of Colorado in Aurora.

The drug protocol consisted of an NS5A inhibitor dubbed ledipasvir and a protease inhibitor, GS-9451, along with pegylated interferon and ribavirin.

Among those who responded to the four-drug regimen quickly and persistently, the rate was even higher at 87%, Everson reported at the meeting of the European Association for the Study of the Liver.

But despite the promise of what he called a "re-treatment protocol," Everson said further development of the regimen is not in the cards.

He did not immediately respond to an email from MedPage Today seeking clarification, but other experts here suggest it may have to do with the perception that pegylated interferon and ribavirin are on the way out.

Meanwhile, ledipasvir and GS-9451 remain in clinical development, according to a spokesman for the developer, Gilead Sciences of Forest City, Calif.

The results of the trial "are not entirely unexpected," commented Heiner Wedemeyer, MD, of Hannover Medical School in Hannover, Germany, who was not involved with the study.

"This specific regimen is not being further developed," he said, but what investigators "learned is that if we add more potent drugs, we can treat more difficult patients. We confirmed that concept."

It seems likely, he said, that the two drugs will continue to be developed for use without interferon and perhaps ribavirin. "The question will be whether we can shorten treatment," Wedemeyer said.

Until 2011, standard therapy for HCV genotype 1 was 48 weeks of pegylated interferon with ribavirin, a regimen regarded as difficult to tolerate with a substantial proportion of treatment failures.

Current standard therapy adds a third drug, one of the protease inhibitors telaprevir (Incivek) or boceprevir (Victrelis), but those medications have their own side effects and risks.

Patients who fail standard treatment – either relapsing or not responding in the first place – need better options, Everson said here.

He and colleagues tested the four drugs (ledipasvir, GS-9451, pegylated interferon, and ribavirin) in a response-guided fashion, enrolling 163 patients, including 52 who had not responded to previous therapy, 28 who had a partial response, and 83 who either relapsed or had viral breakthrough on treatment.

Patients who had undetectable viral RNA at weeks four through 20 of treatment stopped therapy after 24 weeks, while the others stopped ledipasvir and GS-9451 but continued the other two drugs for another 24 weeks.

The 70% rate of undetectable virus 12 weeks after the end of therapy (SVR12) indicated a "fairly robust antiviral effect," Everson said, and response during therapy was "highly predictive " of treatment success.

Among those who had a so-called extended rapid virologic response – no detectable virus from weeks four through 20 – the SVR12 rate was 87%, compared with just 28% among those who did not have such a response.

Everson said that patients with genotype 1b did better than those with genotype 1a, while those with the favorable CC variant of the IL-28B gene did better than those with other versions.

He added that 5% of patients had a serious adverse event during the study and 7.3% stopped treatment because of adverse events, all attributed to the interferon or ribavirin.

The overall pattern of adverse events, he said, was "typical" of what is seen with the two older drugs.

The study was supported by Gilead. Everson reported financial links with the company as well as BMS, Abbott, Roche/Genentech, Vertex, Merck/Schering-Plough Novartis, Janssen/Tibotec, GSK, Eisai, and BioTest.

Wedemeyer reported financial links with Abbott, Achillion, Biolex, BMS, Gilead, Janssen-Cilag, Merck, Novartis, Roche, Siemens, Transgene, and ViiV.

Primary source: European Accociation For the Study of the Liver
Source reference:
Everson GT, et al "Combination of the NS5A inhibitor, GS-5885, the NS3 protease inhibitor, GS-9451, and pegylated interferon plus ribavirin in treatment experienced patients with genotype 1 hepatitis C infection" EASL 2013; Abstract 13.

Source

Hemoglobin May Be Toxic for Diseased Liver

By John Gever, Deputy Managing Editor, MedPage Today

Published: April 29, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM -- High levels of hemoglobin may be dangerous in patients with nonalcoholic fatty liver disease (NAFLD), with bleeding a potential remedy, researchers said here.

NAFLD patients undergoing periodic phlebotomy for 2 years in an open-label, randomized trial showed significant declines in alanine and aspartate aminotransferase (ALT, AST) levels and improvements in liver tissue histology relative to an untreated control group, according to Luca Valenti, MD, of the University of Milan in Italy, and colleagues.

And, in a separate study led by Angela Peltec, MD, of the University of Medicine and Pharmacy in Kishinev, Moldova, NAFLD patients in the highest quartile of hemoglobin (more than 152 g/L) had significantly poorer cardiovascular risk profiles than those in the lowest (less than 128.5 g/L).

The Moldovan group found that patients in the highest hemoglobin quintile had a mean 10-year probability of a major cardiovascular event of 28% according to the Framingham equation, compared with 4% in the lowest quartile (P<0.05).

Both studies were reported at the European Association for the Study of the Liver's annual meeting.

Previous studies have found that NAFLD patients are prone to show a degree of iron overload, Valenti and colleagues noted. Some research has linked hemoglobin levels to the level of liver damage in NAFLD patients, as well as suggesting that excess iron may be overtly hepatotoxic -- that is, not just an epiphenomenon in NAFLD.

A pilot clinical study led by Valenti in 2011 found that phlebotomy reduced serum transaminase levels, prompting the group to conduct a larger, randomized trial.

The Italian researchers recruited 38 patients with iron overload, defined as serum ferritin higher than 250 mg/mL or on the basis of liver histological analysis and blood hemoglobin of more than 11 g/dL. They were randomized either to no iron-directed treatment or to phlebotomy every 2 weeks, with 350 mL of blood taken at each session, until serum ferritin declined to less than 100 mg/mL and transferrin saturation was in the range of 40% to 50%.

All patients also underwent lifestyle counseling as usually provided to NAFLD patients in the Milan clinic.

Heavy drinkers, the severely obese, and patients with hereditary hemochromatosis or non-NAFLD liver diseases were excluded.

Control patients showed slight average declines from baseline in serum ferritin and transferrin saturation, whereas those undergoing phlebotomy had markedly steeper reductions.

At the 2-year evaluation, mean ferritin levels stood at about 600 mg/mL in the control group compared with less than 200 mg/mL in the phlebotomy arm (P<0.005). Similarly, mean transferrin saturation was about 38% in controls versus 28% in the phlebotomy group after 2 years (P<0.05); at baseline, both groups had averages close to 40%.

Both groups had dips in mean ALT and AST levels at the 6-month mark, but levels plateaued or increased in the control group at subsequent evaluations, whereas they continued to decline in the phlebotomy group.

At the 2-year measurement, mean ALT and AST levels in controls were 37 and 28 IU/mL, respectively, compared with 24 and 21 IU/mL in the phlebotomy group (both P<0.05 relative to control), Valenti and colleagues reported.

Also, histologic analysis of liver biopsy samples indicated that 33% of the phlebotomy patients and 11% of the controls (P<0.05) had improvements from baseline during the study period.

There were no significant differences between groups in weight loss or changes in waist circumference.

The Moldovan study was a cross-sectional analysis of 117 NAFLD patients, with data collected for cardiovascular risk prediction according to the Framingham system as well as measurements of blood hemoglobin content.

After adjusting for known cardiovascular risk factors, the odds ratio for having a Framingham risk rated as high (greater than 20%) was 3.45 for the highest versus lowest quartile (95% CI 1.12 to 10.70). For patients in the third quartile (hemoglobin of 140 to 152 g/L), the adjusted odds ratio for high cardiovascular risk was 2.07 (95% CI 1.68 to 10.97) versus the lowest quartile.

High hemoglobin levels were associated with younger patient age, higher blood lipid levels, and increased ALT and AST, Peltec and colleagues reported. But the prevalence of hypertension and type 2 diabetes did not correlate significantly with hemoglobin, nor did body mass index values.

Peltec and colleagues concluded that hemoglobin measurement could be helpful in gauging cardiovascular risk in NAFLD patients, in addition to traditional risk factors.

The Moldovan study was limited by its cross-sectional nature and relatively small enrollment. The study by Valenti and colleagues also had relatively few patients. Neither study used actual clinical outcomes.

Neither study had commercial funding.

Valenti and Peltec reported that they had no relevant financial interests.

Primary source: European Association for the Study of the Liver
Source reference:
Valenti L, et al "Effect of iron depletion on liver damage in nonalcoholic fatty liver disease: preliminary results of a randomized controlled trial" EASL 2013; Abstract 1373.

Additional source: European Association for the Study of the Liver
Source reference:
Peltec A, et al "May hemoglobin be a mediator of increased cardiovascular risk in NAFLD?" EASL 2013; Abstract 1357.

Source

Galectin Inhibitors Reverse Liver Cirrhosis in Preclinical Studies

logo-galectin

- Galectin Therapeutics and Icahn School of Medicine at Mount Sinai Data Presented at the International Liver Congress 2013 -

NORCROSS, Ga., April 29, 2013 /PRNewswire/ -- Galectin Therapeutics (NASDAQ: GALT), the leading developer of therapeutics that target galectin proteins to treat fibrosis and cancer, today released data that was presented on April 27, 2013 at the International Liver Congress in Amsterdam, The Netherlands. The data were generated by the laboratory of Dr. Scott Friedman of the Icahn School of Medicine at Mount Sinai, a world renowned investigator and expert on liver fibrosis. GR-MD-02 and GM-CT-01, drugs that inhibit galectin proteins, were found to reverse the most advanced stage of liver fibrosis, called cirrhosis, in experimental animals given toxin-induced cirrhosis.

"The findings of these experiments show that the anti-galectin drugs had a robust effect on cirrhosis, including reversal of tissue architectural changes in the liver that result from fibrosis as well as reduction in portal hypertension, an important pathophysiological effect of cirrhosis," said Dr. Friedman, Dean for Therapeutic Discovery and Chief, Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai. "The experimental design of these studies provided a very high hurdle for any drug to show effectiveness, and yet both GR-MD-02 and GM-CT-01 passed the test. These drugs are excellent candidates for evaluation in human cirrhosis."

"We are gratified that one of the most prominent investigators in the world has shown that our galectin inhibitors were effective in experimental cirrhosis, the most severe form of liver fibrosis, for which there are no currently approved medical therapies," said Dr. Peter G. Traber, President, Chief Executive Officer and Chief Medical Officer, Galectin Therapeutics. "Along with the multiple studies we have presented on liver fibrosis from fatty liver disease, these findings provide added confidence for the potential of this approach in studies of human liver fibrosis and cirrhosis."

The data presented at the International Liver Congress which is sponsored by the European Association for the Study of the Liver (EASL) are posted on the Company website at http://bit.ly/14xDpKK. Rats were treated with a liver toxin which produced fibrosis that replaced over 25% of the liver tissue and resulted in architectural changes consistent with cirrhosis. While continuing to treat with the liver toxin, rats were treated with either a placebo or four weekly injections of either GR-MD-02 or GM-CT-01. The livers were reviewed by a highly qualified liver pathologist who was unaware of the treatments that the animals had received. Both drugs significantly reduced the amount of fibrotic tissue, and most importantly, reversed the histological findings of cirrhosis. Additionally there was a reduction in the blood pressure in the blood system supplying the liver (portal pressure) in the treated animals. Cirrhosis and portal hypertension are the primary abnormalities that lead to complications and death in humans with liver fibrosis. Galectin previously announced initiation of a Phase 1 clinical trial of GR-MD-02 in patients with fatty liver disease (NASH, non-alcoholic steatohepatitis) with advanced fibrosis which is expected to begin enrolling patients in May 2013 (http://bit.ly/11wj6hr).

About Galectin Therapeutics
Galectin Therapeutics (NASDAQ: GALT) is developing promising carbohydrate-based therapies for the treatment of fibrotic liver disease and cancer based on the Company's unique understanding of galectin proteins, key mediators of biologic function. We are leveraging extensive scientific and development expertise as well as established relationships with external sources to achieve cost effective and efficient development. We are pursuing a clear development pathway to clinical enhancement and commercialization for our lead compounds in liver fibrosis and cancer. Additional information is available at www.galectintherapeutics.com.

Forward Looking Statements
This press release contains, in addition to historical information, forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements relate to future events or future financial performance, and use words such as "may," "estimate," "could," "expect" and others. They are based on our current expectations and are subject to factors and uncertainties which could cause actual results to differ materially from those described in the statements. Factors that could cause our actual performance to differ materially from those discussed in the forward-looking statements include, among others: incurrence of operating losses since our inception, uncertainty as to adequate financing of our operations, extensive and costly regulatory oversight that could restrict or prevent product commercialization, inability to achieve commercial product acceptance, inability to protect our intellectual property, dependence on strategic partnerships, product competition, and others stated in risk factors contained in our SEC filings. We cannot assure that we have identified all risks or that others may emerge which we do not anticipate. You should not place undue reliance on forward-looking statements. Although subsequent events may cause our views to change, we disclaim any obligation to update forward-looking statements.

SOURCE Galectin Therapeutics

Galectin Therapeutics Inc., Peter G. Traber, Chief Executive Officer, (678) 620-3186, ir@galectintherapeutics.com

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PR-Logo-Businesswire

April 29, 2013 01:45 AM Eastern Daylight Time

EASL 2013

STRASBOURG, France--(BUSINESS WIRE)--Regulatory News:

Transgene SA (Paris:TNG) (Euronext Paris: FR0005175080), a biopharmaceutical company that develops targeted immunotherapy products to treat major unmet medical needs in cancer and chronic infectious diseases, announced final data of the Phase 2 HCVac trial of TG4040 for the treatment of genotype 1 chronic hepatitis C (CHC) at an oral presentation of the European Association for the Study of the Liver (EASL) Congress in Amsterdam, the Netherlands.

Professor Heiner Wedemeyer, University of Hanover, Germany and Principal Investigator of the HCVac trial, today presented the final data at EASL and stated: “This trial is unique in the field of hepatitis C, representing one of the largest randomized studies ever investigating an immunotherapeutic product against a persistent infection. It is remarkable that TG4040 induced a decline in HCV viral load and that early response rates of standard therapy with peg-interferon alpha and ribavirin were increased. In addition, very important general findings were made that will help Transgene optimize the future clinical development of TG4040.”

This open label study evaluated in 153 randomized patients two schedules of TG4040 in combination with PegIFNα2a (P) and ribavirin (R) versus P/R alone (Arm A): Arm B with six TG4040 injections initiated 4 weeks after P/R and pre-vaccination Arm C with thirteen TG4040 injections initiated 12 weeks before P/R.

The positive effect of TG4040 was seen with pre-treatment of TG4040 in Arm C. The benefit of pre-treatment was observed as early as one week after initiation of PEG-IFNα/RBV with a 40% improvement in decline of mean HCV RNA viral load. The primary endpoint was met in Arm C with a complete early viral response (cEVR) of 64% as compared to 30% in the control arm (p=0.0037).

The virologic response was sustained over time with a SVR24 of 58% in Arm C, compared to 48% in the control arm.

The key immunologic findings were that induction of MVA and HCV specific T-cell responses were essentially seen in Arm C before the addition of PEG-IFNα/RBV. The viral response seen in Arm C was observed in spite of the development of anti-MVA responses.

Overall, safety was similar across the three arms (percentage of adverse events and grade). The investigation of the four cases of severe blood toxicity led to the conclusion of an exacerbation of IFN-known immune side effects in patients with autoimmune predisposition (see press release of 23rd April 2012).

Philippe Archinard, Chairman and Chief Executive Officer of Transgene, stated: “Today’s oral presentation at EASL once again verifies the high level of scientific and medical interest in Transgene’s immunotherapy products. The final results of the HCVac study demonstrated that a specific vectored immunotherapeutic can improve treatment of CHC. While new treatment paradigms are currently emerging, and are likely to enter the market as early as 2014, Transgene is examining different opportunities for TG4040’s future clinical development. Given the results of our Phase 2 study, immunotherapy with TG4040 may warrant further evaluation in combination with IFN-free direct-acting antivirals treatment regimens once they are approved.”

About TG4040

Transgene’s TG4040 immunotherapeutic product is a recombinant vector based on the MVA virus carrying and expressing three of the major non-structural proteins (NS3, NS4 and NS5B) of the hepatitis C virus (“HCV”). The MVA vector is a highly attenuated strain of vaccinia virus, which has been tested extensively in humans as a vaccine against smallpox and is known to strongly stimulate innate and adaptive immune responses to antigens.

About TG4040 Clinical Development Program

In this Phase 2 HCVac study, a total of 153 treatment-naïve patients were enrolled in 28 sites from Europe, the United States and Israel. Patients were randomized in three arms: one control arm (48 weeks of Peg-IFN/RBV) or one of the two experimental arms. In one experimental arm, the TG4040 dosage (subcutaneous injections at the dose of 107 pfu) was administered six times and Peg-IFN/RBV was given as a 4 week lead-in prior to the initiation of TG4040. In the other experimental arm, the same TG4040 dosage was administered 13 times and Peg-IFN/RBV was introduced twelve weeks after initiation of pre-treatment with TG4040. The HCVac trial evaluated the efficacy and safety of these two different schedules of TG4040 administration in combination with Peg-IFN and RBV as compared to Peg-IFN/RBV alone.

About Transgene

Transgene (NYSE-Euronext: TNG), a member of the Institut Mérieux Group, is a biopharmaceutical company. We create, develop and manufacture targeted immunotherapeutics for the treatment of cancers and infectious diseases. Our products are major technological breakthroughs that use well tolerated viruses to indirectly or directly kill infected or cancerous cells. Our four most advanced products have generated proof of concept data in randomized clinical studies: in lung cancer (TG4010), liver cancer (Pexa-Vec), hepatitis C (TG4040) and HPV-related cervical lesions (TG4001). We have concluded strategic agreements for the development of three of these products: an option agreement with Novartis for the development of TG4010, an in-licensing agreement with US-based Jennerex, Inc. to develop and market Pexa-Vec and a strategic collaboration with EORTC to develop TG4001 in cancer of the oropharynx. We also have a non-exclusive agreement with Sanofi/Genzyme for the future commercial production of our products. Most of our 280 employees are based in Strasbourg, France, and we have operations in Lyon, China and the USA. Additional information about Transgene is available at www.transgene.fr.

Transgene Forward Looking Statements

This press release contains forward-looking statements notably referring to plans for the future development of TG4040 as a treatment against chronic hepatitis C, in combination with new treatments. These plans are subject to changes and uncertainties and we could never be able to develop, manufacture or sell TG4040 in the future. For further information on the risks and uncertainties involved in the testing and development of Transgene’s product candidates, see Trangene’s Document de Référence on file with the French Autorité des marchés financiers on its website at http://www.amf-france.org and on Transgene’s website at www.transgene.fr.

Contacts

Transgene
Philippe Archinard, Chairman & CEO, +33 (0)3 88 27 91 22
Stéphane Boissel, Executive Vice President & CFO, +33 (0)3 88 27 91 02
Elisabetta Castelli, Director IR, +33 (0)3 88 27 91 21
or
MC Services
Raimund Gabriel, +49 89 210 228 30
Shaun Brown, +44 207 148 5998

Source

April 29, 2013

The addition of faldaprevir to pegylated interferon/ribavirin therapy significantly improved rates of sustained virologic response and allowed for shorter treatment duration among patients with chronic hepatitis C in a study presented at the International Liver Congress in Amsterdam.

In the STARTVerso1 study, patients with chronic HCV genotype 1 received 48 weeks of therapy with peginterferon alfa-2a and ribavirin (PEG/RBV) and were randomly assigned either placebo (n=132) for 24 weeks, 120 mg faldaprevir (FDV, Boehringer Ingelheim Pharmaceuticals) (n=259) for 12 or 24 weeks, or 240 mg FDV (n=261) for 12 weeks. HCV RNA below 25 IU/mL after 4 weeks and undetectable RNA at 8 weeks were considered early success among treated patients, and therapy, including PEG/RBV, was stopped at 24 weeks.

Sustained virologic response (SVR) at 12 weeks occurred in more 120-mg (79%) and 240-mg (80%) treated patients than placebo participants (52%, P<.0001). Treatment was stopped at 24 weeks due to early response in 87% and 89% of the 120-mg and 240-mg groups, respectively, compared with 22% of placebo recipients. Among those who stopped treatment early, SVR12 was achieved by 86% of the 120-mg group, 89% of the 240-mg group and 90% of placebo patients.

Serious adverse events occurred at similar rates (6% of placebo recipients; 7% of treated groups), as did treatment discontinuation due to adverse events (4% of the placebo and 120-mg groups; 5% of the 240-mg group). Discontinuation of FDV, but not PEG/RBV, due to adverse events occurred in 1% of the 120-mg group and 3% of the 240-mg group. Anemia, rash and GI issues were reported most commonly.

“Faldaprevir has shown efficacy in a range of genotype-1a and 1b HCV patients with and without cirrhosis,” researcher Peter Ferenci, MD, Medical University of Vienna, said in a press release. “The viral cure rates and potential for shorter treatment duration seen in STARTVerso1 are very encouraging for the many patients currently facing a year of interferon-based treatment.”

For more information:

Ferenci P. #1416: Faldaprevir Plus Pegylated Interferon Alfa-2A and Ribavirin in Chronic HCV Genotype-1 Treatment-Naive Patients: Final Results From STARTVerso1, A Randomized, Double Blind, Placebo-Controlled Phase III Trial. Presented at: The International Liver Congress 2013; April 24-28, Amsterdam.

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